The level of HDL-cholesterol [cholesterol contained in HDL (high density lipoprotein); hereinafter, sometimes abbreviated to “HDL-C”] is known as a negative risk factor in coronary artery diseases. Various drugs has been developed for the purpose of raising that level, but thus developed drugs, such as fibrate type drugs, are not sufficient though they raise HDL-C levels significantly. Besides, such rise in HDL-C levels represents a consequential factor. Recent studies using transgenic mice, etc. have revealed that, as long as the true purpose is to extract cholesterol from foci of arteriosclerosis, what is needed is technology to raise the level of apolipoprotein A-I (hereinafter, sometimes abbreviated to “apo A-I”) that plays a major role in the cholesterol extraction.
Apo A-I in plasma exists for the most part as HDL in the form of complexes with phospholipid, cholesterol, cholesterol ester and so on. These complexes are catabolized mainly in the liver. However, it is known that in some diseases such as hypertriglyceridemia, HDL particles with increased triglyceride (hereinafter, sometimes abbreviated to “TG”) contents are converted into smaller apo A-I particles by various lipases and then catabolized mainly in the kidney. The catabolism in the kidney is achieved as follows: small particles of apo A-I that have been filtered through the uriniferous tubule are re-absorbed in the proximal tubule and then degraded. Kozyraki et al. have been reported that cubilin (GenBank Accession No. AF034611) molecules expressed on the uriniferous tubule epithelium and known to bind to vitamin B12-intrinsic factor complex and LDL receptor-related protein (LRP)-associated protein (hereinafter, sometimes abbreviated to “RAP”) also bind to apo A-I (see, for example, Nature Medicine Vol. 5, No. 6, 656-661 (1999); Proc. Natl. Acad. Sci. USA, Vol. 96, 10158-10163 (1999)). However, relations between the binding of cubilin to apo A-I and plasma apo A-I or HDL concentration, or relations between this binding and arteriosclerosis have not yet been elucidated.
The binding of cubilin to apo A-I may be an important finding for the development of therapeutics for hypo-high density lipoproteinemia, which is a problem in diseases such as high hypertriglyceridemia, and for the development of drugs for treating arteriosclerosis at the root. To specify the apo A-I-binding domain in cubilin molecules is extremely useful, for example, for developing anti-cubilin-apo A-I-binding domain antibody and screening for certain low molecular weight compounds.
Thus, the finding that the apo A-I-binding site is located in a specific region in cubilin molecules is extremely important in view of clinical application, and the identification of this binding site has been eagerly awaited. Furthermore, the raising of serum apo A-I concentration and HDL concentration by administering a substance that inhibits the binding of apo A-I to cubilin partial fragments, and therapeutics for arteriosclerosis comprising such a substance have been eagerly awaited in order to treat hypertriglyceridemia, hypercholesterolemia and arteriosclerotic diseases.